Beta-3-Adrenoceptor Agonists

Mechanism of Action

During the urine storage phase, sympathetic nerve stimulation predominates, noradrenaline is released and activates ꞵ-adrenoceptors in the bladder leading to smooth muscle relaxation and bladder filling. When the bladder is ready to void, parasympathetic stimulation occurs, releasing acetylcholine, which acts on muscarinic M2 and M3 receptors to cause bladder contraction.

Mirabegron and vibegron are potent and selective ꞵ3-adrenoceptor agonists that relax detrusor smooth muscle, enhancing urine storage and reducing urgency and frequency of micturition.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/4j429gk

Fig 1: Mirabegron is a selective β₃-adrenoceptor agonist that relaxes detrusor smooth muscle to increase bladder capacity.

Pharmacokinetic Parameters

The following table describes key pharmacokinetic parameters for ꞵ3-adrenoceptor agonists

Cautions

• Bladder outlet obstruction and/or concomitant antimuscarinics – risk of urinary retention
• Congenital or acquired QT prolongation

Contraindications

• Severe renal or hepatic impairment (GFR <15 mL/min/1.73 m² or Child-Pugh C respectively)

Additional contraindications for mirabegron:

• Mirabegron can increase blood pressure and is contraindicated in patients with severe uncontrolled hypertension (systolic ≥180 mmHg and/or diastolic ≥110 mmHg)
• Haemodialysis
• Moderate hepatic impairment or GFR 15–29 mL/min/1.73 m² with strong CYP3A4 inhibitors

Additional contraindications for vibegron:

• Hereditary galactose intolerance, total lactase deficiency, or glucose–galactose malabsorption

Adverse Effects

Although β₃-adrenoceptor agonists are generally well tolerated, their adverse effect profile differs from that of antimuscarinic agents due to their distinct mechanism of action. Cardiovascular effects, particularly increases in blood pressure, are of particular clinical relevance with mirabegron, whereas vibegron appears to have a more neutral cardiovascular profile. Both agents may cause mild gastrointestinal symptoms and urinary tract infections.

The table below summarises the most clinically relevant adverse effects associated with mirabegron and vibegron, highlighting key differences that may influence prescribing decisions.

Interactions

Mirabegron 

Metabolised by CYP3A4: Strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, clarithromycin): reduce mirabegron dose in mild-moderate renal or hepatic impairment, avoid use in severe renal or moderate hepatic impairment.

Inhibits CYP2D6: monitor for toxicity with CYP2D6 substrates with narrow therapeutic index (e.g. imipramine, desipramine, flecainide)

Inhibits P-gp: P-gp substrates (e.g. digoxin): start digoxin at the lowest dose; monitor serum digoxin levels.

Vibegron

Substrate for CYP3A4: No dose adjustments required for CYP3A4 inducers or inhibitors – metabolism does not play a main role in elimination of vibegron and CYP3A4 is expected to have minimal involvement 

Substrate for P-gp: caution with vibegron and p-gp substrates with narrow therapeutic window (e.g. dabigatran, apixaban, rivaroxaban)

Digoxin: vibegron has shown to increase levels of digoxin – serum digoxin levels should be monitored

References 

1. Mirabegron Astellas 25 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) – (emc)
2. Obgemsa 75 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc)
3. Vibegron | Prescribing information | Incontinence – urinary, in women | CKS | NICE
4. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.